Project Summary: Consistent with the NIDA mission of using science to understand drug abuse and addiction, this proposal serves the long-term objective of localizing and characterizing structural and functional neuropathology in chronic methamphetamine abuse, a widespread condition of major public health importance. The project focuses on diminished capacity for response inhibition in methamphetamine abuse. Impaired response inhibition is a likely manifestation of frontostriatal dysfunction and is believed to perpetuate addiction and to compromise treatment outcome. Specifically, this project will investigate the metabolism of brain regions involved with response inhibition and/or afflicted by methamphetamine abuse. Neurometabolism will be assayed with proton magnetic resonance spectroscopic imaging (1H MRSI), a comparatively underused technology in this condition. Methamphetamine abusers will undergo non-invasive, in vivo 1H MRSI scans just before entering treatment after brief abstinence and will be compared to age- and sex-matched healthy controls. Study endpoints will include levels of the metabolites A/-acetyl compounds, glutamate;+ glutamine + GABA, creatine +'phosphocreatine, choline compounds, and myo-inositol in inferior frontal cortex, anterior cingulate cortex, anterior cingulate white matter, and nucleus accumbens. We will acquire 1H MRSI at shot echo-time permitting us to sample a greater number of neurometabolites from more brain strucures at higher spatial resolution than reported in previous studies. This raises the probability of detecting any metabolite abnormalities that mayattend methamphetamine abuse and allows them to be localized with greater precision in terms of brain structure and tissue type. We will thus capture a wide metabolic profile of the methamphetamine addict's brain at time of entry into treatment. Relevance. Abuse of illicit methamphetamines is a serious public health problem of epidemic proportion in the US and abroad. One (1) possible reason methampetamine addiction is so difficult for many to overcome is that the addict's ability to inhibit him-or herself in seeking drug is thought to be compromised by brain damage. This project will examine the chemistry of parts of the brain thought to be responsible for inhibition and/or damaged by methamphetamine in methamphetamine addicts.[unreadable] [unreadable] [unreadable] [unreadable]